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Nationwide Trends of Hospital Admissionand Outcomes Among Critical LimbIschemia Patients

From 2003–2011

Shikhar Agarwal, MD, MPH, Karan Sud, MD, Mehdi H. Shishehbor, DO, MPH, PHD

ABSTRACT

Fro

ha

Ma

BACKGROUND Critical limb ischemia (CLI) continues to be a major cause of vascular-related morbidity and mortality in

the United States.

OBJECTIVES The study sought to characterize the trends in hospitalization of U.S. patients with CLI from 2003 to 2011,

using the Nationwide Inpatient Sample. We compared the cost utilization and in-hospital outcomes of endovascular and

surgical revascularization procedures for CLI.

METHODS CLI and revascularization procedures were identified using International Classification of Diseases-Ninth

Edition-Clinical Modification codes. In-hospital mortality and amputation were coprimary outcomes. Length of stay (LOS)

and cost of hospitalization were secondary outcomes.

RESULTS We included a total of 642,433 admissions with CLI across 2003 to 2011. The annual rate of CLI admissions

has been relatively constant across 2003 to 2011 (w150 per 100,000 people in the United States). There has been a

significant reduction in the proportion of patients undergoing surgical revascularization from 13.9% in 2003 to 8.8% in

2011, while endovascular revascularization has increased from 5.1% to 11.0% during the same time period. This was

accompanied by a steady reduction in the incidence of in-hospital mortality and major amputation. Compared to surgical

revascularization, endovascular revascularization was associated with reduced in-hospital mortality (2.34% vs. 2.73%,

p < 0.001), mean LOS (8.7 days vs. 10.7 days, p < 0.001), and mean cost of hospitalization ($31,679 vs. $32,485,

p < 0.001) despite similar rates of major amputation (6.5% vs. 5.7%, p ¼ 0.75).

CONCLUSIONS While CLI admission rates have remained constant from 2003 to 2011, rates of surgical reva-

scularization have significantly declined and endovascular revascularization procedures have increased. This has been

associated with decreasing rates of in-hospital death and major amputation rates in the United States. Despite

multiple adjustments, endovascular revascularization was associated with reduced in-hospital mortality compared to

surgical revascularization during 2003 to 2011. (J Am Coll Cardiol 2016;67:1901–13)

© 2016 by the American College of Cardiology Foundation.

I t has been estimated that 10 million individualsare currently suffering from critical limbischemia (CLI) in the United States (1,2). In addi-

tion to pain, decreased quality of life, and immobility,amputation and death are major adverse effects ofCLI (3). Previous data from the Nationwide InpatientSample (NIS) demonstrated a marked rise in endovas-cular revascularization during 1996 to 2005 and wastemporally associated with a reduction in the rates

m the Department of Cardiovascular Medicine, Heart and Vascular Insti

ve reported that they have no relationships relevant to the contents of th

nuscript received January 30, 2016; revised manuscript received Februar

of major amputation (4). However, this relationshipis not causal and may be related to better medicaland overall wound care. Importantly, the rise ofendovascular procedures, in general, has raisedsome concerns (5). We conducted a comprehensiveanalysis using the large nationwide registry from2003 to 2011 to expand on these previous findingsand examine the overall CLI hospital admissions,cost utilization, and outcomes (mortality and major

tute, Cleveland Clinic, Cleveland, Ohio. All authors

is paper to disclose.

y 9, 2016, accepted February 11, 2016.

ABBR EV I A T I ON S

AND ACRONYMS

CI = confidence interval

CLI = critical limb ischemia

HCUP = Healthcare Cost and

Utilization Project

ICD-9-CM = International

Classification of Diseases-Ninth

Edition-Clinical Modification

LOS = length of stay

NIS = Nationwide Inpatient

Sample

OR = odds ratio

PAD = peripheral artery

disease

SES = socioeconomic status

Agarwal et al. J A C C V O L . 6 7 , N O . 1 6 , 2 0 1 6

Critical Limb Ischemia–Related Admissions in the United States A P R I L 2 6 , 2 0 1 6 : 1 9 0 1 – 1 3

1902

amputations) between surgical and endovas-cular procedures for CLI.

METHODS

DATA SOURCE. Data were obtained from theNIS from 2003 to 2011, which is sponsored bythe Agency for Healthcare Research andQuality as a part of the Healthcare Cost andUtilization Project (HCUP). The NIS across2003 to 2011 contains discharge level datafrom approximately 8 million hospitaliza-tions annually from about 1,000 U.S hospi-tals. The NIS is designed to represent a 20%stratified sample of all hospitals in thecountry. Criteria used for stratified samplingof hospitals into the NIS include location

(urban or rural), teaching status, geographic region,patient volume and hospital ownership. Every hos-pital has been classified into small, medium, andlarge size on the basis of the number of bedsavailable for in-hospital admissions. The cutpointsfor classification differ according to geographiclocation of the hospital and the teaching status (6).

SEE PAGE 1914

STUDY POPULATION. The NIS provides up to 15 di-agnoses and 15 procedures for each hospitalizationrecord for the years 2003 to 2009. The number of di-agnoses coded in the database was expanded to 25for the years 2010 to 2011. All these have beencoded using the standard International Classificationof Diseases-Ninth Edition-Clinical Modification(ICD-9-CM) codes. All adult hospitalizations (>18years of age) with a diagnosis code corresponding toCLI were included in our study. The list of diagnosiscodes used to identify patients with CLI and periph-eral artery disease (PAD) is shown in Online Table 1.The first diagnosis in the database is referred to as theprincipal diagnosis and is considered the primaryreason for admission to the hospital. The ICD-9-CMcodes for surgical and endovascular proceduresperformed during the hospitalization are shown inOnline Table 2. Sequential revascularization wasdefined as both endovascular and surgical revascu-larization performed during a single hospital admis-sion. We used the Charlson Comorbidity Score toquantitate the comorbidity of each admitted patienton the basis of 17 categories of diagnoses (7). Inaddition, the NIS database provides 29 Elixhausercomorbidities on each hospital admission, on the basisof standard ICD-9-CM codes (8). These were used toderive the prevalence of hypertension, diabetes,obesity, and chronic kidney disease in our population.

STUDY OUTCOMES. Our study aimed to evaluate thetrend in the CLI hospitalization of adults across2003 to 2011. To calculate the annual rate of admissionsamong CLI patients, we divided the total of number ofhospitalizations in a given year by the U.S. censuspopulation for that year and expressed it as a rate per100,000 U.S. population. This methodology has beendescribed and validated by HCUP and other recentstudies (9,10). We also evaluated the changes in thedistribution of demographic and clinical characteris-tics among these patients. In-hospital mortality andmajor amputation (amputation above the ankle) werecoprimary endpoints of our study. Secondary end-points included resource utilization, which wasassessed by evaluating the trends in revascularizationprocedures, length of stay (LOS), and total cost ofhospitalization across the study period. The NIS data-base provides the total charges associated with eachhospital stay that was claimed by the respective hos-pital. The total charges of each hospital stay wereconverted to cost estimates using the group averageall-payer in-hospital cost and charge informationfrom the detailed reports by hospitals to the Centersfor Medicare and Medicaid Services. All costs andcharges were then converted to projected estimatesfor the year 2015, after accounting for annual infla-tion rates on the basis of consumer price index dataavailable from the Bureau of Labor Statistics (11).Furthermore, we compared the primary and sec-ondary outcomes between the endovascular, surgicaland sequential revascularization in the study cohort,across 2003 to 2011.STATISTICAL ANALYSIS. Survey statistics tradition-ally used to analyze complex semi-random surveydesigns were employed to analyze these data (12,13).Because the data from NIS represent a collection ofscattered hospital clusters, analysis was structured toaccount for a complex, multistage, probability sam-pling. NIS recommends the use of “strata” for con-structing analysis clusters, which include geographiccensus region, hospital ownership, teaching status,urban/rural location and bed size. Furthermore, theanalysis is further stratified into individual hospitals,which serve as primary sampling units for the analysis.In the NIS, each hospital admission is linked to a“discharge weight” that can be utilized to calculateprojected national estimates for all hospital-relatedoutcomes, after accounting for the hierarchical struc-ture of the dataset. To facilitate analysis of trendsacross multiple years, the Agency for HealthcareResearch and Quality has developed new dischargetrend weights (TRENDWT) for NIS data to create na-tional estimates for trends analysis (14). AlthoughTRENDWTwas developed for trends analysis, it can be

FIGURE 1 Annual Rate of CLI and PAD Admissions in the United States

2003 2004 2005 2006 2007 2008 2009 2010 2011Year

2003 2004 2005 2006 2007 2008 2009 2010 2011Year

400

500

600

700

800

PAD

Popu

latio

n Ra

te’ (

Per 1

0000

0 US

Pop

ulat

ion)

050

100

150

CLI P

opul

atio

n Ra

te (P

er 10

0000

US

Popu

latio

n)

010

0000

2000

0030

0000

Num

ber o

f CLI

Adm

issio

ns40

0000

5000

0060

0000

1.2 M

1.4 M

1.6 M

Num

ber o

f PAD

Adm

issio

ns (I

n M

illio

ns)

1.8 M

2.0

M

A

B

(A) Annual rate of critical limb ischemia (CLI) (B) and peripheral artery disease (PAD)

admissions. Bars correspond to the y-axis on the left side of the graph and represent the

projected annual number of admissions. The line corresponds to the y-axis on the right side

of the figure and represents the admission rate expressed as rate per 100,000 U.S.

population calculated using annual census estimates.

J A C C V O L . 6 7 , N O . 1 6 , 2 0 1 6 Agarwal et al.A P R I L 2 6 , 2 0 1 6 : 1 9 0 1 – 1 3 Critical Limb Ischemia–Related Admissions in the United States

1903

used for all analyses as per HCUP. The nonparametrictest for trend across ordered groups by Cuzick (15) wasused to determine the statistical significance of dif-ferences in CLI prevalence across the study period.

Multivariable hierarchical logistic regression anal-ysis with exchangeable matrix was used to determineindependent predictors of in-hospital mortality in thestudy cohort. Covariates included age, sex, race,socioeconomic status (SES) quartile (assessed usingmedian income of the residential zip code), history ofprior amputation, revascularization during hospitali-zation, stump complication, emergency admission,hospital characteristics (region, size, teaching status),comorbidity score, reason for admission, and year ofpresentation. Because the variable “race” had w20%missing data, we used multiple imputation formissing data using ordered logistic regression ac-counting for the clustered nature of the dataset byincorporating hospital characteristics into the multi-ple imputation model. The comparison of primaryand secondary endpoints between endovascular,surgical and sequential revascularization was per-formed using similar multivariable regression anal-ysis and covariates. For regression modeling, LOS andcost of hospitalization were logarithm transformed toeliminate the rightward skew. To avoid the possibilityof type I error due to multiple testing, we report99% confidence intervals (CI) for all our regressionanalyses. All statistical analyses were performed us-ing the statistical software Stata version 13.1 (Stata-Corp, College Station, Texas).

SUBGROUP ANALYSIS. Subgroup analyses were per-formed for death, major amputation, likelihood ofany revascularization (vs. no revascularization), andlikelihood of endovascular revascularization (vs.surgical revascularization) in the study cohort on thebasis of a priori–defined subgroups. Subgroups weredefined on the basis of age, sex, SES quartiles, race,hospital size, type, and location.

RESULTS

HOSPITALIZATION TRENDS. We included a total of642,433 admissions with CLI across 2003 to 2011,which projected to an estimated population of2,999,007 admissions nationally across the studyduration. The annual rate of CLI admissions has beenrelatively constant across 2003 to 2011 (Figure 1A).This was despite an increase in the rate of PAD relatedadmissions during 2003 to 2011 (Figure 1B). There wasa progressive reduction in the mean age of admittedpatients from 2003 to 2011 (Figure 2A). The percentageof patients with CLI <65 years of age admitted to thehospital increased from 34.2% in 2003 to 39.3% in

2011 (p < 0.001) (Figure 2A). Besides this, there was agradual increase in the proportion of males with CLIadmitted to the hospital with a correspondingdecrease in the proportion of females hospitalizedduring the study period (Figure 2B). Table 1 shows thetrend of prevalence of cardiovascular risk factors inthe study cohort during 2003 to 2011. We noted aprogressive increase in hypertension, obesity, dia-betes mellitus, chronic kidney disease as well as prioramputation rates from 2003 to 2011.

Figure 3 shows the primary reason for admission tothe hospital among patients with CLI. Of all patients,

FIGURE 2 Age and Sex Distribution Among CLI Patients

2003 2004 2005 2006 2007 2008 2009 2010 2011Year

6667

6869

70M

ean

Age

(Yea

rs)

3234

36Pe

rcen

t of P

atie

nts w

ith A

ge <

65 Y

ears

3842

40

2003 2004 2005 2006 2007 2008 2009 2010 2011Year

4045

5055

60Pe

rcen

tage

4045

50Pe

rcen

tage

5560

Male

A

B

Female

(A) Mean age (black line, right sided y-axis) as well as the proportion of patients <65

years of age (bars, left sided y-axis) and (B) proportion of males (blue squares) and fe-

males (red circles) among patients admitted with critical limb ischemia (CLI).

Agarwal et al. J A C C V O L . 6 7 , N O . 1 6 , 2 0 1 6

Critical Limb Ischemia–Related Admissions in the United States A P R I L 2 6 , 2 0 1 6 : 1 9 0 1 – 1 3

1904

53.5% of the patients were admitted for primary CLI-related diagnosis. Diabetes mellitus with nonvascularcomplaints (8.6%), septicemia (5.6%), and post-procedure complications (5.2%) were the other sig-nificant reasons for admission to the hospital amongthese patients. There was also a progressive increasein the proportion of patients admitted on an “emer-gent” basis (rather than elective) from 68.7% in 2003to 75.4% in 2011 (p for trend <0.001) (Online Figure 1).

OUTCOMES. Over the study duration, there was asteady reduction in the annual incidence ofin-hospital mortality and major amputation rates(Figure 4A). The annual in-hospital mortality ratereduced from 5.4% in 2003 to 3.4% in 2011 (p for

trend <0.001). Similarly, the annual major amputa-tion rate reduced from 16.7% in 2003 to 10.8% in 2011(p for trend <0.001). In addition, there was a signifi-cant reduction in the LOS (reported in the article asmean � SE) from 10.0 � 0.1 days in 2003 to 8.4 � 0.1days in 2011 (p for trend <0.001) (Figure 4B). How-ever, there was no significant difference in the cost ofhospitalization among CLI patients across the studyduration (p for trend ¼ 0.10) (Figure 4B).

Table 2 shows the predictors of in-hospitalmortality derived from multivariable hierarchicallogistic regression analysis. Older age and female sexwere associated with increased in-hospital mortality.We did not observe any impact of race and SES uponin-hospital mortality. Furthermore, emergent admis-sions were associated with significantly higher mor-tality as compared to elective admissions. A primarypresentation of septicemia, congestive heart failure,and respiratory disease were noted to be stronglypredictive of in-hospital mortality. Presence of stumpcomplication during hospital admission was alsoindependently predictive of in-hospital mortality.Importantly, any revascularization was associatedwith significantly reduced in-hospital mortality in thestudy cohort. There was a significant impact of hos-pital characteristics on in-hospital mortality amongCLI patients (Table 2).

COMPARISON OF REVASCULARIZATION STRATEGIES.

Figure 5 shows the trend of surgical revasculari-zation (Figure 5A), endovascular revascularization(Figure 5B), sequential revascularization (Figure 5C),and revascularization procedures with minor ampu-tations (Figure 5D) across the study period. There wasa significant reduction in the proportion of patientsundergoing surgical revascularization from 13.9% in2003 to 8.8% in 2011 (p for trend <0.001). This wasaccompanied by a corresponding increase in endo-vascular revascularization from 5.1% in 2003 to 11.0%in 2011 (p for trend <0.001). Besides this, there was asmall but statistically significant increase in the inci-dence of sequential revascularization proceduresfrom 1.8% in 2003 to 2.2% in 2011 (p for trend ¼ 0.01).However, there was no significant change in theincidence of revascularization procedures along withminor amputations during 2003 to 2011 (p for trend ¼0.43). Figure 6 shows the trend of primary and sec-ondary endpoints among patients undergoing endo-vascular, surgical, and sequential revascularizationacross 2003 to 2011. Compared to surgical revascu-larization, endovascular revascularization was asso-ciated with significantly reduced in-hospitalmortality (2.34% vs. 2.73%; adjusted odds ratio [OR]:0.69; 99% CI: 0.62 to 0.77) (Figure 6A). Both

TABLE 1 Trend of Cardiovascular Risk Factors in the Study Cohort Across

2003 to 2011

Year Hypertension Obesity DiabetesChronic Kidney

DiseasePrior

Amputation

2003 59.3 4.6 50.8 20.7 11.5

2004 61.2 5.1 50.1 21.4 12.3

2005 62.2 5.5 49.8 23.2 11.3

2006 655 6.6 50.5 30.2 12.3

2007 66.1 7.8 52.3 31.7 12.2

2008 69.7 9.9 52.2 31.3 12.6

2009 71.4 11.7 54.1 34.8 16.2

2010 73.0 12.3 54.3 36.0 16.2

2011 75.2 15.0 56.7 37.8 17.8

All numbers represent percent of total inpatient admissions for critical limb ischemia for aparticular year. Hypertension, diabetes, chronic kidney disease, and diabetes were identified usingElixhauser comorbidities available in the Nationwide Inpatient Sample. Prior amputation wasidentified using the International Classification of Diseases-Ninth Edition-Clinical Modificationcodes V497.0 to V497.7.

FIGURE 3 Reasons for Admission

0 20 40 60

Primary CLIDiabetes-Non-Vascular

SepticemiaPost procedure Complications

CHFRespiratory Disorders

Acute MI/ CADARF

CVA/ TIAFluid / Electrolyte Anomalies

ArrhythmiasHypertension Complications

VTEOther Causes

53.518.55

5.575.21

3.253.05

1.841.160.780.650.640.56

0.5514.69

Percent of All Admissions

The primary reason for admission to the hospital among patients with critical limb ischemia

(CLI). The number beside the each bar denotes the percent of patients presenting with the

corresponding principal diagnosis. ARF ¼ acute renal failure; CAD ¼ coronary artery dis-

ease; CHF ¼ congestive heart failure; CVA ¼ cerebrovascular accident; MI ¼ myocardial

infarction; TIA ¼ transient ischemic attack; VTE ¼ venous thromboembolism.

J A C C V O L . 6 7 , N O . 1 6 , 2 0 1 6 Agarwal et al.A P R I L 2 6 , 2 0 1 6 : 1 9 0 1 – 1 3 Critical Limb Ischemia–Related Admissions in the United States

1905

endovascular and surgical revascularization wereassociated with similar rates of major amputation(6.50% vs. 5.65%; adjusted OR: 0.99; 99% CI: 0.91 to1.07) (Figure 6B). LOS among patients undergoingendovascular revascularization was 8.70 � 0.12 days,which was significantly lower than the LOS in thesurgical revascularization cohort (10.70 � 0.13 days;adjusted OR: 0.80; 99% CI: 0.79 to 0.81) (Figure 6C).Similarly, the cost (mean � SE) of hospitalizationamong patients undergoing endovascular revascu-larization was $31,679 � $449, which was significantlylower than the cost of hospitalization in the surgicalrevascularization cohort ($32,485 � $550; adjustedOR: 0.95; 99% CI: 0.94 to 0.96) (Figure 6D). Comparedto endovascular and surgical revascularization,sequential revascularization was associated withsignificantly higher in-hospital mortality, majoramputation, and cost of hospitalization (Figure 6).Although the mean LOS among patients undergoingsequential revascularization was higher than thoseundergoing endovascular revascularization, itappeared similar between the sequential and surgicalrevascularization groups (Figure 6).SUBGROUP ANALYSIS. Table 3 shows the subgroupanalyses for death, major amputation, likelihood ofany revascularization and likelihood of endovascularrevascularization on the basis of a priori–definedsubgroups. Compared to younger patients, older pa-tients had a higher risk of death or major amputationand were more likely to undergo a revascularizationprocedure. Females had higher in-hospital mortalitybut a lower rate of major amputation compared tomales. Among those who underwent a revasculari-zation procedure, females were more likely to un-dergo endovascular intervention as compared tomales. Although there was no significant impact ofrace on in-hospital mortality, blacks and other raceshad significantly higher rates of major amputationand lower rates of revascularization, compared towhites. Similarly, higher SES was associated withlower rates of major amputation, compared to lowerSES categories. There was a significant heterogeneityapparent in outcomes between the different hospi-tals. Urban teaching hospitals had significantly higherrates of in-hospital mortality, major amputation aswell as revascularization rates compared to ruralhospitals. Similarly, large-sized hospitals had higherrates of in-hospital mortality, major amputation andrevascularization rates compared to small-sized hos-pitals. Furthermore, there were significant differ-ences in hospital outcomes between variousgeographic regions, shown in Table 3.

Online Figure 2 shows the changing trend of CLIadmissions among blacks (Online Figure 2A),

uninsured patients (Online Figure 2B), patients withMedicaid as primary insurance (Online Figure 2C) andthose residing in lowest SES quartile zip codes(Online Figure 2D). During the course of the studyduration, there has been an increase in the proportionof uninsured patients (p for trend <0.001) as well aspatients with Medicaid as primary insurance (p fortrend <0.001). However, there have been no signifi-cant changes in trends in admission of black patients

FIGURE 4 Primary and Secondary Outcomes Among CLI Patients

2003 2004 2005 2006 2007 2008 2009 2010 2011Year

2003 2004 2005 2006 2007 2008 2009 2010 2011Year

Major Amputation Death

35

79

Perc

enta

ge o

f All

Adm

its11

1317

1510

000

1500

0M

ean

Cost

of H

ospi

taliz

atio

n ($

)20

000

3000

025

000

56

Mea

n Le

ngth

of S

tay

(Day

s)7

810

9

A

B

(A) The trend of annual incidence of in-hospital mortality and major amputation rates

among patients hospitalized with critical limb ischemia (CLI). (B) The trend of annual mean

length of stay (black line, right sided y-axis) and mean cost of hospitalization (bars, left

sided y-axis) among patients hospitalized with CLI.

TABLE 2 Multivariable Hierarchical Logistic Regression Model

for In-Hospital Mortality Among Patients With CLI Admitted to

Hospitals During 2003 to 2011

OddsRatio

99% ConfidenceInterval

Age 1.028 1.027–1.030

Female (vs. male) 1.10 1.06–1.14

Race

White Reference

Black 1.01 0.96–1.07

Other race 1.02 0.96–1.07

SES quartiles

Quartile 1 Reference

Quartile 2 1.03 0.98–1.08

Quartile 3 0.98 0.93–1.03

Quartile 4 1.00 0.95–1.07

Prior amputation 0.57 0.53–0.62

Any revascularization 0.81 0.77–0.86

Stump complication 1.83 1.63–2.04

Emergency admission (vs. elective) 1.40 1.32–1.49

Hospital region

Northeast Reference

Midwest 0.73 0.68–0.79

South 0.87 0.81–0.93

West 0.96 0.89–1.04

Hospital type

Rural Reference

Urban nonteaching 1.08 1.01–1.16

Urban teaching 1.20 1.1–1.30

Hospital size

Small Reference

Medium 1.12 1.02–1.23

Large 1.23 1.13–1.34

Charlson Comorbidity Score

0–2 Reference

3 1.07 1.03–1.12

4 1.29 1.23–1.36

5þ 1.52 1.45–1.60

Reason for admission

Septicemia 7.14 6.81–7.49

Hypertension complication 2.07 1.74–2.46

Acute MI/CAD 2.72 2.48–2.98

CHF 5.69 2.67–12.14

CVA/TIA 2.68 2.35–3.06

VTE 1.73 1.42–2.09

Respiratory disease 3.51 3.29–3.74

AKI 2.34 2.09–2.63

Year of presentation

2003 Reference

2004 0.90 0.83–0.98

2005 0.82 0.75–0.90

2006 0.75 0.69–0.81

2007 0.62 0.57–0.67

2008 0.61 0.56–0.66

2009 0.59 0.54–0.64

2010 0.55 0.50–0.60

2011 0.47 0.43–0.52

AKI ¼ acute kidney injury; CAD ¼ coronary artery disease; CHF ¼ congestive heartfailure; CLI ¼ critical limb ischemia; CVA ¼ cerebrovascular accident; MI ¼myocardial infarction; SES ¼ socioeconomic status; TIA ¼ transient ischemic

Agarwal et al. J A C C V O L . 6 7 , N O . 1 6 , 2 0 1 6

Critical Limb Ischemia–Related Admissions in the United States A P R I L 2 6 , 2 0 1 6 : 1 9 0 1 – 1 3

1906

(p for trend ¼ 0.65) or those residing in lowest quar-tile SES zip codes (p for trend ¼ 0.62).

DISCUSSION

In the current study we evaluated and compared theoverall trends, outcomes, and resource utilizationamong endovascular, surgical, and sequentialrevascularization procedures among patientsadmitted with CLI in the contemporary era using alarge comprehensive nationwide database. We haveseveral important findings (Central Illustration). First,the annual rate of CLI admissions has been relativelyconstant across 2003 to 2011, despite a progressive

attack; VTE ¼ venous thromboembolism.

FIGURE 5 Trends of Revascularization Strategies Among CLI Patients

2003 2004 2005 2006 2007 2008 2009 2010 2011Year

04

812

16

010

000

2000

030

000

4000

0

Perc

enta

ge o

f All

Adm

its

Num

ber o

f Sur

gica

l Rev

ascu

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atio

ns2003 2004 2005 2006 2007 2008 2009 2010 2011

Year

04

812

16

010

000

2000

030

000

4000

0

Perc

enta

ge o

f All

Adm

its

Num

ber o

f End

ovas

cula

r Rev

ascu

lariz

atio

ns

2003 2004 2005 2006 2007 2008 2009 2010 2011Year

04

812

16

010

000

2000

030

000

4000

0

Perc

enta

ge o

f All

Adm

its

Num

ber o

f Seq

uent

ial R

evas

cula

rizat

ions

2003 2004 2005 2006 2007 2008 2009 2010 2011Year

04

812

16

010

000

2000

030

000

4000

0

Perc

enta

ge o

f All

Adm

its

Num

ber o

f Rev

ascu

lariz

atio

ns W

ith M

inor

Am

puta

tions

A B

C D

Trends of (A) surgical revascularization, (B) endovascular revascularization, (C) sequential revascularization, and (D) revascularization procedures with minor amputa-

tions among patients hospitalized with critical limb ischemia (CLI) during 2003 to 2011. Bars denote the estimate expressed as a percent of all admissions and

correspond to the left sided y-axis. Black line denotes the trend of the projected number of revascularization procedures performed annually and corresponds to the

right-sided y-axis.

J A C C V O L . 6 7 , N O . 1 6 , 2 0 1 6 Agarwal et al.A P R I L 2 6 , 2 0 1 6 : 1 9 0 1 – 1 3 Critical Limb Ischemia–Related Admissions in the United States

1907

increase in the rate of PAD admissions. Second,besides primary CLI related diagnoses, diabetesmellitus with nonvascular complaints, septicemiaand post-procedure complications were the othersignificant reasons for admission to the hospitalamong CLI patients. Third, there was a progressiveincrease in the proportion of patients admitted on anemergent basis during 2003 to 2011. Fourth, therehas been a reduction in the proportion of patientsundergoing surgical revascularization, accompaniedby a corresponding increase in endovascular revas-cularization during the study duration. Fifth, therewas a reduction in the incidence of in-hospitalmortality, major amputation as well as mean LOSduring the study duration. Last, despite similar ratesof major amputation, the endovascular approach

was associated with reduced in-hospital mor-tality, mean LOS and mean cost of hospitalizationcompared to surgical revascularization, aftermultiple adjustments.

Several studies have examined patterns in treat-ment of PAD in the past (16–20). Rowe et al. (4)demonstrated a progressive decline in surgicalrevascularization accompanied by an increase in therates of endovascular revascularization during 1996to 2005. Similarly, Nowygrod et al. (18) demonstratedan increased utilization of endovascular procedurescombined with a decrease in open revascularizationsurgery and a decrease in major amputation ratesfrom 1998 to 2003. Although both studies showeddecreasing amputation rates with increasing endo-vascular procedures, this relationship has in general

FIGURE 6 Trends in Primary and Secondary Outcomes

2003 2004 2005 2006 2007 2008 2009 2010 2011Year

2003 2004 2005 2006 2007 2008 2009 2010 2011Year

2003 2004 2005 2006 2007 2008 2009 2010 2011Year

2003 2004 2005 2006 2007 2008 2009 2010 2011Year

12

34

5Pe

rcen

t Mor

talit

y

04

812

Perc

ent A

mpu

tatio

n

48

1216

Mea

n Le

ngth

of S

tay

(Day

s)

3000

035

000

4000

045

000

5000

0M

ean

Cost

of A

dmiss

ion

($)

5500

0

Adjusted OR (99% CI)1) 0.69 (0.62-0.77)2) 0.56 (0.46-0.65)3) 0.81 (0.71-0.93)

Adjusted OR (99% CI)1) 0.99 (0.91-1.07)2) 0.79 (0.75-0.88)3) 0.80 (0.71-0.88)

Adjusted Ratio of Observed LOS (99% CI)1) 0.80 (0.79-0.81)2) 0.78 (0.77-0.79)3) 0.99 (0.98-1.01)

Adjusted Ratio of Observed Cost (99% CI)1) 0.95 (0.94-0.96)2) 0.84 (0.83-0.85)3) 0.88 (0.87-0.89)

A B

C D

Surgical Endovascular Sequential

Comparison of primary and secondary outcomes among endovascular (circles), surgical (squares), and sequential revascularization (triangles) procedures. A to D

demonstrate the trend of annual in-hospital mortality, major amputation, mean length of stay, and mean cost of hospitalization among patients undergoing

endovascular, surgical, and sequential revascularization procedures, respectively. Only those patients who underwent revascularization during the hospitalization were

included in this analysis. All adjusted estimates were calculated after adjusting for age, sex, imputed race, socioeconomic status, emergency admits, hospital location,

hospital size, hospital teaching status, insurance status, Charlson Comorbidity Score, and primary reason for admission. 1) Adjusted effect estimate (with 99% CIs)

comparing endovascular with surgical revascularization; 2) adjusted effect estimate (with 99% CIs) comparing endovascular with sequential revascularization; and

3) denotes adjusted effect estimate (with 99% CIs) comparing surgical with sequential revascularization. CI ¼ confidence interval; OR ¼ odds ratio.

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been considered noncausal and likely attributableto aggressive medical therapy and wound care.However, our results indicate that the annual rate ofadmission among CLI patients remained relativelyconstant. Interestingly, we noted that there was asignificant increase in PAD related admissions during2003 to 2011. This rise in PAD might be secondary tothe rise in the prevalence of cardiovascular risk fac-tors, as observed in our study. An increase in the rateof PAD related admissions, with a constant rate of CLIrelated admissions, might suggest early detection ofPAD among population by their physicians, leading toimproved management and the relative stabilizationof the CLI rates. In addition, we noted a reduction inthe amputation rates over time, despite a constantrate of CLI and an increasing rate of PAD related

admissions. This suggests that other factors beyondmedical therapy might be responsible for decreasingrates of amputation over this period. This may besecondary to increasing availability and improve-ment in endovascular revascularization techniques inthe United States (21). We observed a progressiveincrease in the proportion of patients admitted on anemergent basis rather than elective basis across 2003to 2011. This may be secondary to higher rates ofrevascularization in the elderly with more complexdisease, changing patterns in presentation among CLIpatients, or because of changing patterns in insur-ance coverage among patients making emergencyroom their primary source of healthcare. Regardlessof the reasons, this underscores the increasinghealthcare cost and burden imposed by these

TABLE 3 Subgroup Analyses for Death, Major Amputation, Likelihood of Any Revascularization, and Likelihood of Endovascular

Revascularization in the Study Cohort on the Basis of A Priori–Defined Subgroups

Death Major AmputationLikelihood of AnyRevascularization

Likelihood of EndovascularRevascularization*

Age

<65 yrs Reference Reference Reference Reference

$65 yrs 1.91 (1.84–1.99) 1.26 (1.23–1.30) 1.20 (1.17–1.23) 1.24 (1.19–1.28)

Sex

Male Reference Reference Reference Reference

Female 1.15 (1.11–1.19) 0.92 (0.90–0.94) 0.98 (0.97–1.01) 1.29 (1.24–1.33)

Hospital size

Small Reference Reference Reference Reference

Medium 1.12 (1.02–1.22) 1.20 (1.10–1.31) 1.26 (1.06–1.50) 0.99 (0.71–1.39)

Large 1.21 (1.11–1.32) 1.33 (1.23–1.44) 1.67 (1.41–1.98) 0.91 (0.66–1.24)

Hospital type

Rural Reference Reference Reference Reference

Urban nonteaching 1.07 (0.99–1.15) 1.08 (0.98–1.20) 1.91 (1.54–2.38) 0.96 (0.77–1.21)

Urban teaching 1.18 (1.09–1.29) 1.27 (1.15–1.41) 2.64 (2.13–3.28) 0.91 (0.72–1.15)

Socioeconomic status

Quartile 1 Reference Reference Reference Reference

Quartile 2 1.03 (0.98–1.08) 1.01 (0.97–1.05) 1.08 (1.03–1.13) 0.90 (0.84–0.95)

Quartile 3 1.00 (0.94–1.05) 0.89 (0.86–0.93) 1.05 (0.99–1.10) 0.90 (0.82–0.97)

Quartile 4 1.03 (0.97–1.09) 0.81 (0.77–0.84) 1.07 (1.01–1.13) 0.97 (0.86–1.08)

Race

White Reference Reference Reference Reference

Black 1.00 (0.95–1.05) 1.48 (1.42–1.54) 0.92 (0.88–0.96) 0.99 (0.90–1.07)

Other race 0.99 (0.94–1.05) 1.06 (1.01–1.11) 0.89 (0.83–0.95) 1.19 (1.07–1.32)

Hospital location

Northeast Reference Reference Reference Reference

Midwest 0.72 (0.67–0.78) 1.02 (0.94–1.10) 0.91 (0.82–1.01) 1.33 (1.03–1.72)

South 0.85 (0.79–0.91) 1.39 (1.30–1.50) 0.94 (0.85–1.04) 1.27 (1.02–1.57)

West 0.95 (0.88–1.02) 1.15 (1.06–1.24) 0.99 (0.87–1.12) 1.04 (0.81–1.34)

Values are adjusted odds ratio (95% confidence interval). The adjusted odds ratios were derived using multivariable hierarchical logistic regression modeling, which incor-porated nature of admission (emergency vs. elective), reason for admission (as shown in Figure 3), prior amputation, presence of a stump complication, Charlson ComorbidityScore, and year of presentation, in addition to the subgroups shown in the table. *The likelihood of endovascular revascularization was derived using a cohort of patient thatunderwent endovascular or surgical revascularization and therefore estimates the likelihood of endovascular revascularization in comparison to the likelihood of surgicalrevascularization during the hospitalization.

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patients and the need for increased emphasis onquality of care (22).

Approximately one-half of the hospital admissionsin our study population were related to primary CLI-related diagnoses. The remaining one-half of admis-sions was due to other non–CLI-related causes. Inaddition, we recognized that several of these non-CLIdiagnoses such as acute myocardial infarction, cere-brovascular accident, respiratory disease, congestiveheart failure, and acute kidney injury were associatedwith significantly elevated risk for in-hospital mor-tality. It must be emphasized that patients with CLIharbor an elevated atherosclerotic burden in multiplevascular beds, predisposing them to increasedvascular morbidity and mortality (1,2). Multiplestudies have demonstrated marked escalation of riskof short- and long-term mortality with coexisting CLIand other atherosclerotic diseases such as coronaryartery disease or cerebrovascular disease (6,23–27).

There have been multiple studies in the last decadeexamining various aspects of PAD and CLI in the lastdecade (9,28–33). Similar to earlier studies examiningtrends among PAD and CLI patients, we observed acontinued trend towards a decline in in-hospitalmortality and major amputation rates among pa-tients admitted with CLI. We observed impressivereduction in in-hospital mortality (relative reduction37%) and major amputation (relative reduction 35%)over the course of the study duration. This periodalso witnessed an increase in the number of endo-vascular revascularization procedures accompaniedby a simultaneous decline in the number of surgicalrevascularization procedures. Review of the currentliterature shows heterogeneous estimates forproportion of patients with CLI undergoing revascu-larization (34–36). Although several of these studiesare robust in terms of included data and researchconduct, the differences from our study might be

CENTRAL ILLUSTRATION U.S. Trends in CLI Hospital Admissions and Outcomes

Agarwal, S. et al. J Am Coll Cardiol. 2016;67(16):1901–13.

The salmon line (closed circles) shows the trend of critical limb ischemia (CLI) admissions in the United States during 2003 to 2011. These hospital admissions

correspond to the y-axis on the left side of the figure and have been expressed as number of admissions per 100,000 United States population calculated using annual

census estimates. All other lines correspond to the y-axis on the right side of the figure and represent the proportion of all CLI admissions expressed as a percentage.

During the study period, there was a decline in the surgical revascularization (maroon line [diamonds]) with a corresponding increase in endovascular revascularization

(purple line [triangles]). This was associated with a significant decrease in in-hospital mortality (orange line [open circles]) and major amputations (teal line [squares]).

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secondary to different treatment practices in theUnited States versus other countries. In addition tointernational differences, there has been a well-documented regional variation in the use of lowerextremity revascularization procedures for CLI inthe United States (34,37). As noted in these studies,the intensity of vascular care including the per-centage of revascularization procedures amongCLI patients varied significantly among various

U.S. regions. On an average, the proportion ofMedicare beneficiaries with CLI (requiring amputa-tion) who underwent revascularization was ratherlow during 2003 to 2006 (7.8% endovascular and3.3% surgical).

The last decade also witnessed a substantialdecrease in the mean LOS among patients admittedwith CLI. Although the adjusted cost of hospitaliza-tion appeared to be relatively unchanged among the

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entire cohort during 2003 to 2011, endovascularrevascularization procedures seemed to be associatedwith smaller cost of hospitalization as compared tosurgical revascularization procedures. This findingwas similar to that reported in the resource utilizationanalysis from the BASIL (Bypass versus Angioplastyin Severe Ischemia of the Leg) trial, where bypasssurgery was associated with higher inpatient treat-ment costs as compared to balloon angioplasty at1-year follow up (38). Patient-specific variables alongwith outcomes over a 30-day follow-up period,especially readmission rates, would be necessary tounderstand implications of these observations in adefinitive manner. Further exploration of these mat-ters would be vital with the widespread imple-mentation of the Affordable Care Act and as thepenalties for 30-day readmissions are invoked uni-versally (39,40).

Despite similarities to earlier studies, our study hasseveral unique features, which provide importantinsight into the contemporary management of CLI.Our study uses a large (n ¼ 642,433) well-validateddataset with most contemporary (2003 to 2011) ana-lyses providing insight into the latest trends in prev-alence, outcomes, and resource utilization in CLI.Unlike several prior studies, our study is on the basisof an all insured as well as uninsured patients ratherthan being limited to Medicare or insured, patientpopulations only (28,30,33). The majority of studies inthis area are heterogeneous with inclusion of patientswith PAD and CLI (9,28,30,33). In contrast, our studyprovides insights and trends specific to patients withCLI. In addition, our manuscript has evaluated bothcost and LOS associated with open surgery and endo-vascular revascularization among patients admittedwith CLI. Furthermore, to the best of our knowledge,our study is the only one that has presented trends ofutilization of sequential therapy as well as revascu-larization in conjunction with minor amputation.Sequential revascularization strategy was associatedwith higher in-hospital mortality, major amputationas well as higher cost of hospitalization as compared toendovascular or surgical revascularization. This wasprobably because of a higher disease burden in thesepatients, necessitating multiple treatment strategiesfor complete revascularization.

In addition to a detailed perspective on the trendsin treatment and outcomes among CLI patients, ourstudy also provides some additional data that mightform the basis of future studies. There were sex-based disparities in treatment and outcomes evidentin our analysis. Females were observed to have higherin-hospital mortality but a lower rate of major am-putations compared to males. Among those who

underwent a revascularization procedure, femaleswere more likely to undergo endovascular interven-tion as compared to males. These observations aresimilar to those reported by Lo et al. (21) using NISdata from an earlier time period. Possibly, the inverseassociation of CLI admissions with improved medicaltherapy remains hypothetical. Other factors such associoeconomic factors, access to health care system,and degree of people with adequate health insurancemay be important in mediating these associations. Wefound racial and SES-based disparities evident in ourcohort. Compared to white patients, blacks had ahigher incidence of major amputations and lowerincidence of revascularization procedures. Similarly,low-SES patients had higher rates of major amputa-tion compared to high-SES patients. The impact ofSES on medical care delivery and outcomes has beenextensively explored in the area of coronary arterydisease and cerebrovascular disease (12,13). It is verylikely that several factors that govern this relation-ship in other atherosclerotic diseases also apply toCLI. However, these have yet to be comprehensivelyand systematically evaluated. Furthermore, our studydemonstrated significant institutional heterogeneityin the treatments and outcomes in CLI patients. Dis-parities in outcomes between teaching andnonteaching hospitals as well as large and smallhospitals can be attributed to increased complexity ofthe case mix at larger tertiary care hospitals. Inaddition, our study demonstrated significant differ-ences in mortality, amputation rates and revascular-ization practices across various geographic regions. Itis unclear if these differences were secondary to anincreased prevalence of CLI in particular regions,differences in presentation/severity, differences inrisk factor profiles, differences in regional patterns ofcare, or a combination of these factors.

STUDY LIMITATIONS. Our study has several impor-tant limitations that are inherent to large adminis-trative databases. First, there may be errors in codingof diseases or procedures; however, these would mostlikely impact both surgical and endovascular revas-cularization. Second, because the unit of analysis inthe NIS database is “unique admission” rather than“unique patient,” it is possible that one patient mighthave been represented more than once, in case ofrepeat admission for recurrent admissions. Third, thisis a retrospective observational study, which may besubject to traditional biases of observational studiessuch as selection bias. Fourth, the database does notcapture the procedures that were performed on anoutpatient visit. More recently, stand-alone outpa-tient facilities have increased, and more complex

PERSPECTIVES

COMPETENCY IN SYSTEMS-BASED PRACTICE:

Despite an increase in hospital admissions for PAD,

the number of admissions for CLI remained constant

during the years 2003 to 2011. Among patients

admitted with CLI over this period, there was an in-

crease in endovascular revascularization, decline in

surgical revascularization, decrease in major amputa-

tions and lower mortality.

TRANSLATIONAL OUTLOOK: Further studies are

needed to understand the reasons for and conse-

quences of disparities in risk factor profiles, severity of

ischemia at presentation, patterns of care, and out-

comes between various geographic regions and types

of hospitals.

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patients may be treated in these centers. Last, NISdoes not provide details about anatomic characteris-tics that are important in deciding the mode ofrevascularization in CLI patients. It was also notpossible to determine the type and invasiveness ofthe surgical or endovascular therapy using the NISdatabase. It is possible that simple lesions werepreferentially treated with endovascular therapy,whereas more complex lesions were treated usingsurgical therapy, leading to obvious differences inoutcomes. Alternatively, it may be likely that thefindings underestimate the impact of endovasculartherapy, as sicker patients with higher comorbiditiesand poor targets were more likely to undergo endo-vascular procedures. Although the comparison ofoutcomes was adjusted for Charlson ComorbidityScore, it is possible that differences might arise due toresidual confounding. Furthermore, due to changesin coding practices during the study duration, thedata on smoking has been traditionally felt to be un-reliable in the NIS database. Hence, trends on smok-ing prevalence were not reported, as these were feltto be inaccurate.

CONCLUSIONS

CLI is a complex disease with significant morbidityand mortality. There has been a significant increase inthe utilization of endovascular revascularization witha corresponding decline in surgical revascularization,accompanied by a decrease in in-hospital death andmajor amputation rates in the United States during

2003 to 2011. Despite similar rates of major amputa-tion, endovascular revascularization was associatedwith reduced in-hospital mortality, mean LOS andmean cost of hospitalization compared to surgicalrevascularization. Although the results are encour-aging, there remain significant disparities and gaps inthe care of CLI patients that must be addressed.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Mehdi H. Shishehbor, Department of CardiovascularMedicine, Cleveland Clinic, 9500 Euclid Avenue,J3-05, Cleveland, Ohio 44195. E-mail: shishem@ccf.org.

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KEY WORDS critical limb ischemia,endovascular interventions, peripheral arterydisease

APPENDIX For supplemental tables andfigures, please see the online version of thisarticle.